Pyridine and pyrazine derivative for the treatment of chronic bronchitis

Abstract

The present invention provides pyridine and pyrazine derivatives which restore or enhance the function of mutant and/or wild type CFTR to treat cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD, opioid induced). Pharmaceutical compositions comprising such derivatives are also encompassed.

We claim: 
     
       1. A method for the treatment of chronic bronchitis in a subject in need thereof, comprising administering an effective amount of at least one compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A is N or CR 4a ; 
         R 1  is H; C 1 -C 8  alkyl optionally substituted by one or more halogen atoms; C 2 -C 8  alkenyl; C 2 -C 8  alkynyl; C 3 -C 10  cycloalkyl; C 5 -C 10  cycloalkenyl; —C 1 -C 4  alkyl-C 3 -C 8  cycloalkyl; C 1 -C 8  alkoxy optionally substituted by one or more halogen atoms; halogen; SO 2 NR′R 9 ; SO 2 R 10 ; S—C 1 -C 8  alkyl optionally substituted by one or more halogen atoms; S—C 6 -C 14  aryl; CN; NR 11 R 12 ; C(O)NR 13 R 14 ; NR 13 SO 2 R 15 ; NR 13 C(O)R 15 , CO 2 R 15 , —(C 0 -C 4  alkyl)-C 6 -C 14  aryl; or —(C 0 -C 4  alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; 
         R 2  is C 1 -C 4  haloalkyl; 
         R 3  and R 4a  are each independently H or C 1 -C 8  alkyl optionally substituted by one or more halogen atoms; 
         R 4  is H, or C 1 -C 8  alkyl optionally substituted with one or more halogen atoms; 
         R 5  is —(CH 2 ) m —NR 17 R 18 , —(CH 2 ) m —OR′; C 1 -C 8  alkoxy optionally substituted by one or more halogen atoms; —(C 0 -C 4  alkyl)-CO 2 R 15 ; —(C 0 -C 4  alkyl)-C 6 -C 14  aryl or −3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the —(C 0 -C 4  alkyl)-C 6 -C 14  aryl and —(C 0 -C 4  alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; 
         R 6  is C 1 -C 8  alkyl optionally substituted by one or more halogen atoms; C 3 -C 10  cycloalkyl; —C 0 -C 4  alkyl-C 3 -C 8  cycloalkyl; C 1 -C 8  alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; —(C 0 -C 4  alkyl)-C 6 -C 14  aryl; or —(C 0 -C 4  alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, —(C 0 -C 4  alkyl)-C 6 -C 14  aryl and —(C 0 -C 4  alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; or 
         R 6  is H, and R 5  is —(CH 2 ) m —NR 17 R 18 , —(CH 2 ) m —OR′, C 1 -C 8  alkoxy optionally substituted by one or more halogen atoms; —(C 0 -C 4  alkyl)-C 6 -C 14  aryl; —(C 0 -C 4  alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or —(C 0 -C 4  alkyl)-CO 2 R 15 , wherein —(C 0 -C 4  alkyl)-C 6 -C 14  aryl and —(C 0 -C 4  alkyl)-3 to 14 membered heterocyclic group groups are each optionally substituted by one or more Z substituents; or 
         R 4  and R 6  together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system; or 
         R 4  and R 5  together form an oxo group (C═O) and R 6  is C 1 -C 4  alkyl optionally substituted by one or more halogen atoms; C 1 -C 4  alkoxy optionally substituted by one or more halogen atoms; —(C 0 -C 4  alkyl)-C 6 -C 14  aryl; or —(C 0 -C 4  alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or 
         R 5  and R 6  together with the carbon atoms to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; or 
         R 4  and R 5  and R 6  together with the carbon atoms to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; 
         R′ is H, or C 1 -C 8  alkyl optionally substituted with one or more halogen atoms; 
         m is 0, 1, 2 or 3; 
         R 8 , R 11 , R 13  and R 17  are each independently H, C 1 -C 8  alkyl optionally substituted by one or more halogen atoms, C 3 -C 10  cycloalkyl or —(C 1 -C 4  alkyl)-C 3 -C 8  cycloalkyl; 
         R 9 , R 10 , R 12 , R 14 , R 15 , and R 18  are each independently H; C 1 -C 8  alkyl optionally substituted by one or more halogen atoms; C 2 -C 8  alkenyl; C 2 -C 8  alkynyl; C 3 -C 10  cycloalkyl; C 5 -C 10  cycloalkenyl; —C 1 -C 4  alkyl-C 3 -C 8  cycloalkyl; —(C 0 -C 4  alkyl)-C 6 -C 14  aryl; or —(C 0 -C 4  alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or 
         R 8  and R 9 , R 11  and R 12 , R 13  and R 14 , and R 17  and R 18  together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents; 
         Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C 1 -C 6  alkyl optionally substituted by one or more OH groups or NH 2  groups, C 1 -C 6  alkyl optionally substituted by one or more halogen atoms, C 1 -C 6  alkoxy optionally substituted by one or more OH groups or C 1 -C 4  alkoxy, (SO 2 )NR 19 R 21 , (SO 2 )R 21 , C(O)NR 19 R 21 , NR 19 R 21 , C(O)OR 19 , C(O)R 19 , SR 19 , OR 19 , oxo, CN, NO 2 , halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; 
         R 19  and R 21  are each independently H; C 1 -C 8  alkyl; C 3 -C 8  cycloalkyl; C 1 -C 4  alkoxy-C 1 -C 4  alkyl; (C 0 -C 4  alkyl)-aryl optionally substituted by one or more groups selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy and halogen; (C 0 -C 4  alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C 1 -C 6  alkyl and C(O)C 1 -C 6  alkyl; (C 0 -C 4  alkyl)-O-aryl optionally substituted by one or more groups selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy and halogen; and (C 0 -C 4  alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C 1 -C 6  alkyl or C(O)C 1 -C 6  alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C 1 -C 4  alkoxy, C(O)NH 2 , C(O)NHC 1 -C 6  alkyl or C(O)N(C 1 -C 6  alkyl) 2 ; or 
         R 19  and R 21  together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O) 2 -aryl; S(O) 2 —C 1 -C 6  alkyl; C 1 -C 6  alkyl optionally substituted by one or more halogen atoms; C 1 -C 6  alkoxy optionally substituted by one or more OH groups or C 1 -C 4  alkoxy; and C(O)OC 1 -C 6  alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C 1 -C 6  alkyl, C 1 -C 6  haloalkyl or C 1 -C 6  alkoxy. 
       
     
     
       2. The method according to  claim 1 , wherein A is CR 4a . 
     
     
       3. The method according to  claim 1 , wherein
 R 1  is C 1 -C 8  alkyl optionally substituted by one or more halogen atoms; C 1 -C 8  alkoxy optionally substituted by one or more halogen atoms; halogen; NR 11 R 12 , C 6 -C 14  aryl; or —(C 0 -C 4  alkyl)-5 to 6 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclic groups are each optionally substituted by one or more Z substituents. 
 
     
     
       4. The method according to  claim 1 , wherein
 R 1  is C 1 -C 4  alkyl optionally substituted by one or more halogen atoms; C 1 -C 4  alkoxy optionally substituted by one or more halogen atoms; or halogen. 
 
     
     
       5. The method according to  claim 1 , wherein
 R 1  is aryl, wherein aryl is phenyl optionally substituted by one or more Z substituents. 
 
     
     
       6. The method according to  claim 1 , wherein
 R 2  is CF 3 . 
 
     
     
       7. The method according to  claim 1 , wherein
 R 4  is H or C 1 -C 4  alkyl optionally substituted by one or more halogen atoms; 
 R 5  is C 1 -C 4  alkoxy optionally substituted by one or more halogen atoms; —(CH 2 ) m —NR 17 R 18 , —(CH 2 ) m —OR′; or —(C 0 -C 4  alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl heterocyclyl groups is optionally substituted by one or more Z substituents; 
 R 6  is C 1 -C 4  alkyl optionally substituted by one or more halogen atoms; C 1 -C 4  alkoxy optionally substituted by one or more halogen atoms; or —(C 0 -C 4  alkyl)-C 6 -C 14  aryl wherein the aryl is optionally substituted by one or more Z substituents; or 
 R 4  and R 6  together with the carbon atoms to which they are bound form a 3 to 6 membered carbocyclic ring system; or 
 R 5  and R 6  together with the carbon atoms to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; 
 m is 0 or 1; 
 R 17  and R 18  are each independently H or C 1 -C 8  alkyl optionally substituted by one or more halogen atoms. 
 
     
     
       8. The method according to  claim 1 , wherein
 A is CR 4a ; 
 R 1  is C 1 -C 4  alkyl optionally substituted by one or more halogen atoms; or C 1 -C 4  alkoxy optionally substituted by one or more halogen atoms; 
 R 2  is CF 3 ; 
 R 3  is H, CH 3  or CF 3 ; 
 R 4  is H or Me; 
 R 4a  is H; 
 R 5  is —NR 17 R 18  or OH, and 
 R 6  is C 1 -C 4  alkyl optionally substituted by one or more halogen atoms. 
 
     
     
       9. A method for the treatment of chronic bronchitis in a subject in need thereof, comprising administering an effective amount of at least one compound of Formula II, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein 
         A is N or CR 4a ; 
         R 4a  is H or C 1 -C 4  alkyl; 
         R 1  is C 1 -C 8  alkyl optionally substituted by one or more halogen atoms; C 1 -C 8  alkoxy optionally substituted by one or more halogen atoms; halogen; NR 11 R 12 ; C 6 -C 14  aryl; or —(C 0 -C 4  alkyl)-5 to 6 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclic groups are each optionally substituted by one or more Z substituents; 
         R 11  is H, C 1 -C 8  alkyl optionally substituted by one or more halogen atoms; C 3 -C 10  cycloalkyl; or —(C 1 -C 4  alkyl)-C 3 -C 8  cycloalkyl; 
         R 12  is H; C 1 -C 8  alkyl optionally substituted by one or more halogen atoms; C 2 -C 8  alkenyl; C 2 -C 8  alkynyl; C 3 -C 10  cycloalkyl; C 5 -C 10  cycloalkenyl; —C 1 -C 4  alkyl-C 3 -C 8  cycloalkyl; —(C 0 -C 4  alkyl)-C 6 -C 14  aryl; or —(C 0 -C 4  alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or 
         R 11  and R 12  together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents; 
         Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C 1 -C 6  alkyl optionally substituted by one or more OH groups or NH 2  groups, C 1 -C 6  alkyl optionally substituted by one or more halogen atoms, C 1 -C 6  alkoxy optionally substituted by one or more OH groups or C 1 -C 4  alkoxy, (SO 2 )NR 19 R 21 , (SO 2 )R 21 , C(O)NR 19 R 21 , NR 19 R 21 , C(O)OR 19 , C(O)R 19 , SR 19 , OR 19 , oxo, CN, NO 2 , halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; 
         R 19  and R 21  are each independently H; C 1 -C 8  alkyl; C 3 -C 8  cycloalkyl; C 1 -C 4  alkoxy-C 1 -C 4  alkyl; (C 0 -C 4  alkyl)-aryl optionally substituted by one or more groups selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy and halogen; (C 0 -C 4  alkyl)-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C 1 -C 6  alkyl and C(O)C 1 -C 6  alkyl; (C 0 -C 4  alkyl)-O-aryl optionally substituted by one or more groups selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy and halogen; and (C 0 -C 4  alkyl)-O-3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C 1 -C 6  alkyl or C(O)C 1 -C 6  alkyl; wherein the alkyl groups are optionally substituted by one or more halogen atoms, C 1 -C 4  alkoxy, C(O)NH 2 , C(O)NHC 1 -C 6  alkyl or C(O)N(C 1 -C 6  alkyl) 2 ; or 
         R 19  and R 21  together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10-membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(O) 2 -aryl; S(O) 2 —C 1 -C 6  alkyl; C 1 -C 6  alkyl optionally substituted by one or more halogen atoms; C 1 -C 6  alkoxy optionally substituted by one or more OH groups or C 1 -C 4  alkoxy; and C(O)OC 1 -C 6  alkyl, wherein the aryl and heterocyclic substituent groups are optionally substituted by C 1 -C 6  alkyl, C 1 -C 6  haloalkyl or C 1 -C 6  alkoxy; 
         R 3  is H or CH 3 ; 
         R 101  is 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       10. A method for the treatment of chronic bronchitis in a subject in need thereof, comprising administering an effective amount of at least one compound selected from the group consisting of:
 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; 
 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; 
 3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; 
 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; and 
 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       11. The method according to  claim 10 , wherein the compound is 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide having the following structure 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       12. The method according to  claim 10 , wherein the compound is 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide having the following structure 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       13. The method according to  claim 1 , wherein the compound is in free form. 
     
     
       14. The method according to  claim 1 , wherein the compound is a pharmaceutically acceptable salt. 
     
     
       15. The method according to  claim 1  further comprising administration of a second drug substance. 
     
     
       16. The method according to  claim 15 , wherein the second drug substance is an osmotic agent, an ENaC blocker, an anti-inflammatory agent, a bronchodilatory agent, an antihistamine agent, an anti-tussive agent, an antibiotic agent and/or a DNase drug substance. 
     
     
       17. The method according to  claim 15 , wherein the second drug substance is administered separately, before, simultaneously with, or after the other drug substance. 
     
     
       18. The method according to  claim 10 , wherein the compound is in free form. 
     
     
       19. The method according to  claim 10 , wherein the compound is a pharmaceutically acceptable salt. 
     
     
       20. The method according to  claim 10  further comprising administration of a second drug substance. 
     
     
       21. The method according to  claim 20 , wherein the second drug substance is an osmotic agent, an ENaC blocker, an anti-inflammatory agent, a bronchodilatory agent, an antihistamine agent, an anti-tussive agent, an antibiotic agent and/or a DNase drug substance. 
     
     
       22. The method according to  claim 20 , wherein the second drug substance is administered separately, before, simultaneously with, or after the other drug substance.